peoniflorin and Memory-Disorders

Alzheimer's disease (AD) is a neurodegenerative disease, associated with progressive cognitive impairment and memory loss. In the present study, we examined the protective effects of paeoniflorin against memory loss and cognitive decline in lipopolysaccharide (LPS)-induced mice. Treatment with paeoniflorin alleviated LPS-induced neurobehavioral dysfunction, as confirmed by behavioral tests, including the T-maze test, novel-object recognition test, and Morris water maze test. LPS stimulated the amyloidogenic pathway-related proteins (amyloid precursor protein, APP; β-site APP cleavage enzyme, BACE; presenilin1, PS1; presenilin2, PS2) expression in the brain. However, paeoniflorin decreased APP, BACE, PS1, and PS2 protein levels. Therefore, paeoniflorin reverses LPS-induced cognitive impairment via inhibition of the amyloidogenic pathway in mice, which suggests that paeoniflorin may be useful in the prevention of neuroinflammation related to AD.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Cognitive Dysfunction; Disease Models, Animal; Glucosides; Lipopolysaccharides; Maze Learning; Memory Disorders; Mice; Mice, Transgenic; Monoterpenes

To explore the delayed neuroprotection induced by paeoniflorin (PF), the principal component of Paeoniae radix prescribed in Chinese medicine, and its underlying mechanisms in rats subjected to vascular dementia (VD).. A rat model of VD was induced by bilateral common carotid arteries occlusion (BCCAO). Low-dose or high-dose PF (20 or 40 mg/kg once per day) was administrated for 28 days after VD. The behavioral analysis of rat was measured by water morris. Regional cerebral blood volume (rCBV), regional cerebral blood flflow (rCBF) and mean transit time (MTT) were measured in the bilateral hippocampus by perfusion-weighted imaging (PWI). The levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) were measured by commercially available enzyme-linked immunosorbent assay kits. Protein levels were evaluated by western blot analysis. mRNA levels were evaluated by real time-polymerase chain reaction. Western blotting was used to estimate p65 translocation.. The behavioral analysis showed that PF could decrease the escape latency time (P<0.05), and increase the residence time of the original platform quadrant and the across platform frequency in water maze in VD rats (P<0.05). Likewise, PF remarkably promoted the rCBV (P<0.05), rCBF and decreased per minute MTT (P<0.05) in hippocampus of VD rats. Furthermore, PF decreased the release of IL-1β, IL-6 and TNF-α as well as inhibited the mRNA expression of IL-1β, IL-6 and TNF-α in the hippocampus of VD rats (P<0.05 or P<0.01). PF also could decrease the protein expressions of inducible nitric oxide synthase and cyclooxygenase-2 in the hippocampus of VD rats (P<0.05 or P<0.01). In addition, PF signifificantly inhibited the nuclear factor κB (NF-κB) pathway in the hippocampus of VD rats.. PF signifificantly attenuates cognitive impairment, improves hippocampus perfusion and inhibits inflflammatory response in VD rats. In addition, the anti-inflflammatory effects of PF might be due to inhibiting the NF-κB pathway. PF may be a potential clinical application in improving VD.

Topics: Animals; Cerebrovascular Circulation; Cognitive Dysfunction; Cyclooxygenase 2; Dementia, Vascular; Down-Regulation; Glucosides; Hippocampus; Inflammation Mediators; Male; Maze Learning; Memory Disorders; Monoterpenes; Nitric Oxide Synthase Type II; Rats, Sprague-Dawley; RNA, Messenger; Transcription Factor RelA

Alzheimer's disease (AD) is associated with the inflammatory response in response to amyloid β-peptide (Aβ). Previous studies have suggested that paeoniflorin (PF) shows anti-inflammatory and neuroprotective effects in inflammation-related diseases. However, the impacts of PF on AD have not been investigated. In the present study, we showed that a 4-week treatment with PF could significantly inhibit Aβ burden, Aβ-induced over activation of astrocytes and microglia, downregulation of proinflammatory cytokines, and upregulation of anti-inflammatory cytokines in the brain. In addition, we demonstrated that chronic treatment with PF inhibited the activation of glycogen synthase kinase 3β (GSK-3β) and reversed neuroinflammtory-induced activation of nuclear factor-kappa B (NF-κB) signaling pathways. Moreover, PF exerted inhibitory effects on NALP3 inflammasome, caspase-1, and IL-1β. Collectively, in the present study, we demonstrated that PF exhibits neuroprotective effects in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (APP/PS1) mice via inhibiting neuroinflammation mediated by the GSK-3β and NF-κB signaling pathways and nucleotide-binding domain-like receptor protein 3 inflammasome. Thus, these results suggest that PF might be useful to intervene in development or progression of neurodegeneration in AD through its anti-inflammatory and anti-amyloidogenic effects.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Glucosides; Inflammation; Inflammation Mediators; Male; Memory Disorders; Mice; Mice, Transgenic; Monoterpenes; Paeonia; Plaque, Amyloid; Presenilin-1

Peoniflorin (PEF), a monoterpene glycoside isolated from the aqueous extract of the dry root of Paeonia, possesses wide pharmacological effects in nervous system. In this study, by using a developed rat model of hippocampal dysfunction induced by intrahippocampal injection of Abeta((1-42)) oligomers, we investigated whether PEF exerted protection against Abeta-induced neurotoxicity. A stereotactic intrahippocampal bilateral injection of Abeta((1-42)) (5 microg per side) was performed in Sprague-Dawley rats (250-280 g). Abeta((1-42))-exposed rats showed remarkable memory impairment in Morris water maze test and neuronal apoptosis by in situ terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling in hippocampus. Chronic treatment with PEF (7.5, 15 and 30 mg/(kg day), for 20 days, intraperitoneally) significantly and dose-dependently attenuated cognitive deficit, ameliorated cell apoptosis in Abeta((1-42))-treated rats. The neuroprotective effect of PEF was closely associated with its activities of maintenance of [Ca(2+)](i) homeostasis, increase of reduced glutathione (GSH) content, suppression of NOS activity and nitric oxide (NO) level, decrease of carbonyl protein (CP) and malondialdehyde (MDA) levels. These results suggested that PEF possessed the activity of prevention of the neurotoxicity induced by Abeta((1-42)) and might exert beneficial action for the treatment of Alzheimer's disease (AD).

Topics: Amyloid beta-Peptides; Animals; Apoptosis; Benzoates; Bridged-Ring Compounds; Calcium; Glucosides; Glutathione; Hippocampus; Male; Malondialdehyde; Maze Learning; Memory; Memory Disorders; Monoterpenes; Neuroprotective Agents; Nitric Oxide; Nitric Oxide Synthase; Oxidative Stress; Peptide Fragments; Protein Carbonylation; Rats; Rats, Sprague-Dawley

Chronic cerebral hypoperfusion, a mild ischemic condition, is associated with the cognitive deficits of AD. Paeoniflorin (PF), a major constituent of peony root, was proved to be neuroprotective in middle cerebral artery occlusion model. In this study, we investigated whether PF could attenuate chronic cerebral hypoperfusion-induced learning dysfunction and brain damage in rat. Seven weeks after permanent bilateral occlusion of the common carotid arteries, the rats were tested in the Morris water maze. Subsequently, the animals were sacrificed and neurons, astrocytes and microglias were labeled with immunocytochemistry in hippocampus. PF at the dose of 2.5 mg/kg ameliorated cerebral hypoperfusion-related learning dysfunction and prevented CA1 neuron damage. Chronic cerebral hypoperfusion increased the immunoreactivity of astrocytes and microglias in hippocampus. The increase was prevented by PF at the dose of 2.5 mg/kg. Cerebral hypoperfusion also increased expression of nuclear factor-kappaB (NF-kappaB), mostly in astrocytes, but not in neurons. With the treatment of PF (2.5 mg/kg), NF-kappaB immunostaining was diminished in hippocampus. Our results demonstrated that PF could attenuate cognitive deficit and brain damage induced by chronic cerebral hypoperfusion and that suppression of neuroinflammatory reaction in brain might be involved in PF-induced neuroprotection.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Benzoates; Biomarkers; Brain Damage, Chronic; Brain Ischemia; Bridged-Ring Compounds; Cerebral Infarction; Disease Models, Animal; Dose-Response Relationship, Drug; Encephalitis; Gliosis; Glucosides; Hippocampus; Infarction, Middle Cerebral Artery; Learning Disabilities; Male; Maze Learning; Memory Disorders; Monoterpenes; Nerve Degeneration; Neuroglia; Neurons; Neuroprotective Agents; NF-kappa B; Rats; Treatment Outcome